Myeloid-derived suppressor cells (MDSC) can suppress immunity and promote tumorigenesis, and their abundance is associated with poor prognosis. In this study, we show that SUMO1/sentrin-specific peptidase 1 (SENP1) regulates the development and function of MDSC. SENP1 deficiency in myeloid cells promoted MDSC expansion in bone marrow, spleen, and other organs. Senp1(-/-) MDSC showed stronger immunosuppressive activity than Senp1(+/+) MDSC; we observed no defects in the differentiation of myeloid precursor cell in Senp1(-/-) mice. Mechanistically, SENP1-mediated regulation of MDSC was dependent on STAT3 signaling. We identified CD45 as a specific STAT3 phosphatase in MDSC. CD45 was SUMOylated in MDSC and SENP1 could deconjugate SUMOylated CD45. In Senp1(-/-) MDSC, CD45 was highly SUMOylated, which reduced its phosphatase activity toward STAT3, leading to STAT3-mediated MDSC development and function. These results reveal a suppressive function of SENP1 in modulating MDSC expansion and function via CD45-STAT3 signaling axis.
Significance: These findings show that increased SUMOylation of CD45 via loss of SENP1 suppresses CD45-mediated dephosphorylation of STAT3, which promotes MDSC development and function, leading to tumorigenesis.
[1]Shanghai Jiao Tong Univ, Sch Med, Dept Biochem & Mol Cell Biol, Shanghai Key Lab Tumor Microenvironm & Inflammat, Shanghai, Peoples R China.
[2]Shanghai Jiao Tong Univ, Renji Hosp Affiliated, State Key Lab Oncogenes & Related Genes, Sch Med, Shanghai, Peoples R China.
[3]Shanghai Jiao Tong Univ, Shanghai Inst Immunol, Dept Immunol & Microbiol, Sch Med, Shanghai, Peoples R China.
[4]Shanghai Jiao Tong Univ, Renji Hosp Affiliated, Dept Urol, Sch Med, Shanghai, Peoples R China.
[5]Shanghai Univ Tradit Chinese Med, Sch Pharm, Shanghai, Peoples R China.
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